The Effects of Activation and Blockade of Delta Opioid Receptors on the Acquisition of Responding for an Opioid‐Associated Stimulus

Abstract

Drug‐associated stimuli take on conditioned reinforcing properties that promote drug‐seeking and relapse. Previously, we have demonstrated that daily systemic injections of SNC80 (delta opioid receptor agonist) resulted in dose‐dependent increases in responding for the opioid‐associated stimulus. In the current experiment, we assessed the extent to which activating and/or blocking delta opioid receptors via a systemic injection of SNC80 or naltrindole, respectively, modified the conditioned reinforcing properties of an opioid‐associated stimulus. We hypothesized that a pre‐session injection of SNC80 would increase the conditioned reinforcing properties of the remifentanil‐associated stimulus; however, an injection of naltrindole would have no effect, and an injection of naltrindole would block the ability of SNC80 to enhance the conditioned reinforcing properties of the stimulus. First, we exposed rats to 20 i.v. infusions of remifentanil (3.2 ug/kg/infusion) and 20 stimulus presentations that were delivered response‐independently each day for 5 days. For the experimental group (Paired Conditioning), the remifentanil infusions and stimulus presentations were delivered concurrently. The control group (Random control) received the same number of infusions and stimulus presentations, but they were not explicitly paired. For the next 7 sessions (acquisition), we tested the extent to which the stimulus functioned as a conditioned reinforcer by allowing rats to freely respond via a nosepoke for presentations of the remifentanil‐associated stimulus only. On the fourth acquisition session, rats received one of the following combinations of injections: (a) vehicle + vehicle, (b) vehicle + naltrindole (3.2 mg/kg), (c) vehicle + SNC80 (3.2 mg/kg), or (d) SNC80 (3.2 mg/kg) + naltrindole (3.2 mg/kg). We found that rats in the Paired Pavlovian Conditioning group responded for the remifentanil‐associated stimulus significantly more than controls (p= 0.003, hp2= 0.15). Responding for remifentanil‐paired stimuli depended on treatment condition (p < 0.001, hp2= 0.35). Post‐hoc tests revealed that SNC80 administration increased responding for the remifentanil‐associated stimulus relative to all other treatment conditions (p’s < 0.001). These findings demonstrated that a remifentanil‐associated stimulus takes on conditioned reinforcing properties and that the conditioned reinforcing properties of the stimulus was augmented by delta opioid receptor activation and these effects were blocked via naltrindole. These findings support previous work that delta opioid receptors play a role in mediating conditioned reinforcing properties of drug‐associated stimuli.